Tumor Necrosis Factor α (TNF-α) is a major inflammatory cytokine, which has been initially identified in 1975 for its ability to trigger necrosis of cutaneous mouse fibrosarcoma in vivo. At variance with prior knowledge, a growing body of evidence in mouse models indicates that TNF produced by cancer and/or stromal cells may favour the establishment of a pro-inflammatory microenvironment, modulating specific anti-cancer immune response and enhancing tumor angiogenesis, tumor progression and metastasis.
Different studies have illustrated the role of TNF in skin tumor formation. As compared to their wild-type counterparts, TNF-deficient mice, TNF-R1-deficient mice and, albeit to a lesser extent, TNF-R2-deficient mice are reluctant to carcinogen-induced benign skin tumor (i.e., papillomas) formation. However, malignant progression from skin papilloma to carcinoma is similar in wild-type and TNF-deficient mice. The conclusion was that TNF plays an important role in the early stages of tumor promotion, most likely through its ability to trigger local inflammation. Indeed, the characterization of TNF-deficient mouse skin indicates an increased CD8 T cell infiltration upon DMBA/TPA treatment as compared to their wild-type counterparts.
The role of TNF in melanoma remains controversial. Injection of high levels of recombinant TNF triggers necrosis of melanoma, not only in mice, but also in humans and is currently used in isolated limb perfusion in the clinic (Balkwill F. 2009). The pro-necrotic TNF effect is likely dependent on its ability to induce apoptosis of endothelial cells. In sharp contrast, it has been recently shown that TNF, which is produced in patients treated with BRAF V600E inhibitors (Wilmott et al, 2014), may confer resistance of human melanoma by increasing Twist1 levels (Menon, D. R. et al 2013). The role of TNF in melanoma has been further investigated in mice using B16 melanoma cells, which do not express TNF endogenously. Whereas ectopic membrane TNF on B16 cells triggers TNF-R2-dependent pro-tumoral myeloid cell death, and subsequent impaired in vivo melanoma growth, ectopic expression of soluble TNF at low levels by B16 has opposite effect on melanoma growth in mice, most likely through its ability to enhance tumor angiogenesis (Li, B. et al, 2009). Both B16 cell growth and tumor angiogenesis are reduced in TNF-R2-deficient mice. Moreover, lung invasion of intravenously injected B16 melanoma cells is decreased in TNF−/− and TNF-R2−/− mice, indicating that TNF likely enhances melanoma dissemination in a TNF-R2-dependent manner (Chopra, M. et al, 2013). Vaccination towards TNF triggers self anti-TNF antibodies and inhibits lung invasion of intravenously injected B16 melanoma cells. Similar data have been obtained by injecting anti-TNF neutralizing antibodies or soluble TNF-R1, indicating that TNF blockade may represent an interesting strategy to prevent melanoma metastasis. A recent study showed that TNF deficiency can delay tumor growth in a spontaneous mouse model of BRAF V600E melanoma (Smith M P et al., 2014) In humans, different case reports have documented the occurrence of melanoma in patients with autoimmune disorders treated with anti-TNF. However, recent meta-analyses do not confirm the association of anti-TNF treatments and an increased melanoma incidence.
TNF is involved in the modulation of both innate and specific immune responses. Whereas TNF is produced by Natural Killers (NK), it reduces the susceptibility of B16 melanoma cells to NK cells, at least in part, by enhancing MHC class I expression at the cell surface of melanoma cells (Palmieri G et al, 1992). Conflicting results have been published on the role of TNF in the CD8 T cell immune response towards cancer cells. On the one hand, TNF acts as an effector molecule in CD8 T cell-triggered cell death of cancer cells and a co-stimulatory cytokine able to enhance naive CD8 T cell proliferation and cytokine secretion. In addition, TNF is required for the establishment of anti-tumor immune response by facilitating dendritic cell maturation as well as CD8 T cell activation and tumor infiltration. On the other hand, TNF triggers TNFR2-dependent activation-induced cell death (AICD) in CD8 T cells, thus likely limiting immune response duration. Moreover, TNF may behave as an immunosuppressive cytokine, facilitating the increased number of regulatory T and B cells as well as Myeloid-Derived Suppressor Cells (MDSC). In an adoptive transfer therapy protocol of specific CD8 T cells in mice, TNF could induce dedifferentiation of melanoma cells associated with a decrease of melanocytic antigen expression, likely contributing to tumor relapse. The latter study indicates that TNF putatively contributes to melanoma immune escape.
Recently, some tumor blood vessels, designated tumor high endothelial venules (HEVs), which mediate lymphocyte entry, have been found in human breast and melanoma (Martinet, L., 2012) tumors. HEVs display cuboidal morphology and express high levels of sulfated carbohydrate ligands for L-selectin (CD62L), which mediates lymphocyte rolling along endothelium. In humans, the density of HEVs (denoted as MECA79+ vessels) is highly correlated with CD8 T cell tumor infiltration and inflammation as evaluated by an increased expression of pro-inflammatory cytokines. In this context, the TNF expression level and its putative role in CD8 T cell melanoma infiltration and HEV differentiation have not been investigated.